A phase I study of the combination of atezolizumab, tiragolumab, and stereotactic body radiation therapy in patients with metastatic multiorgan cancer

Background Immunotherapy targeting the PD-1/PD-L1 pathway is a standard of care in a number of metastatic malignancies, but less than a fifth of patients are expected to respond to ICIs (Immune Checkpoint Inhibitors). In a clinical trial, combining the anti-TIGIT (T cell immunoreceptor with Ig and ITIM domains) Mab (monoclonal antibody) tiragolumab with atezolizumab improved outcomes in non-small cell lung cancer. In preclinical models, SBRT (Stereotactic Body Radiation Therapy) could increase expression levels of the inhibitory co-receptors TIGIT and PD-L1. We aim to assess the combination of tiragolumab with atezolizumab and SBRT in metastatic, previously treated by ICIs, non-small cell lung cancer, head and neck cancer, bladder cancer, and renal cell cancer. Methods This phase I study (ClinicalTrials.gov NCT05259319) will assess the efficacy and safety of the combination of atezolizumab with tiragolumab and stereotactic body radiation therapy in patients with histologically proven metastatic non-small cell lung cancer, renal cell cancer, bladder cancer, and head and neck cancer previously treated. First part: 2 different schedules of SBRT in association with a fixed dose of atezolizumab and tiragolumab will be investigated only with metastatic non-small cell lung cancer patients (cohort 1). The expansion cohorts phase will be a multicentric, open-label study at the recommended scheme of administration and enroll additional patients with metastatic bladder cancer, renal cell cancer, and head and neck cancer (cohort 2, 3 and 4). Patients will be treated until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient refusal in the absence of progression or intolerance. The primary endpoint of the first phase is the safety of the combination in a sequential or concomitant scheme and to determine the expansion cohorts phase recommended scheme of administration. The primary endpoint of phase II is to evaluate the efficacy of tiragolumab + atezolizumab + SBRT in terms of 6-month PFS (Progression-Free Survival). Ancillary analyses will be performed with peripheral and intratumoral immune biomarker assessments. Trial registration This study is registered on ClinicalTrials.gov: NCT05259319, since February 28th, 2022. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-023-11534-6.


Management guidelines for diarrhea or colitis:
Event Management

Diarrhea or colitis, Grade 1
Continue tiragolumab and atezolizumab.Initiate symptomatic treatment.Endoscopy is recommended if symptoms persist for > 7 days.Monitor closely.

Diarrhea or colitis, Grade 2
Withhold tiragolumab and atezolizumab for up to 12 weeks after event onset.a Initiate symptomatic treatment.Patient referral to GI specialist is recommended.For recurrent events or events that persist > 5 days, initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral prednisone.If event resolves to Grade 1 or better, resume tiragolumab and atezolizumab.b If event does not resolve to Grade 1 or better while withholding tiragolumab and atezolizumab, permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c Diarrhea or colitis, Grade 3

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Withhold tiragolumab and atezolizumab for up to 12 weeks after event onset.Refer patient to GI specialist for evaluation and confirmatory biopsy.

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Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.

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If event resolves to Grade 1 or better, resume tiragolumab and atezolizumab.b If event does not resolve to Grade 1 or better while withholding tiragolumab and atezolizumab, permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c

Diarrhea or colitis, Grade 4
• Permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c Refer patient to GI specialist for evaluation and confirmation biopsy.• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.• If event does not improve within 48 hours after initiating corticosteroids, consider adding an immunosuppressive agent.
If event resolves to Grade 1 or better, taper corticosteroids over  1 month.GI = gastrointestinal.a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.The acceptable length of the extended period of time must be agreed upon by the investigator and the Medical Monitor.b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed.c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.Patients can be rechallenged with tiragolumab and atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor.

Hypophysitis (panhypopituitarism), Grade 2 or 3
Withhold tiragolumab and atezolizumab for up to 12 weeks after event onset.a Refer patient to endocrinologist.Perform brain MRI (pituitary protocol).Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV methylprednisolone and convert to 1 2 mg/kg/day oral prednisone or equivalent upon improvement.Initiate hormone replacement if clinically indicated.If event resolves to Grade 1 or better, resume tiragolumab and atezolizumab.b If event does not resolve to Grade 1 or better while withholding tiragolumab and atezolizumab permanently discontinue tiragolumab and atezolizumab.c For recurrent hypophysitis, treat as a Grade 4 event.

Hypophysitis (panhypopituitarism), Grade 4
Permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c Refer patient to endocrinologist.Perform brain MRI (pituitary protocol).Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.Initiate hormone replacement if clinically indicated.MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone.a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.The acceptable length of the extended period of time must be agreed upon by the investigator and the Medical Monitor.b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed.c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.Patients can be re-challenged with tiragolumab and atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor.

Management Guidelines for Ocular Events
Event Management

Ocular event, Grade 1
Continue tiragolumab and atezolizumab.Patient referral to ophthalmologist is strongly recommended.Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive therapy.
If symptoms persist, treat as a Grade 2 event.

Ocular event, Grade 2
Withhold tiragolumab and atezolizumab for up to 12 weeks after event onset.a Patient referral to ophthalmologist is strongly recommended.Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive therapy.
If event resolves to Grade 1 or better, resume tiragolumab and atezolizumab.b If event does not resolve to Grade 1 or better while withholding tiragolumab and atezolizumab, permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c

Ocular event, Grade 3 or 4
Permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c Refer patient to ophthalmologist.Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral prednisone.If event resolves to Grade 1 or better, taper corticosteroids over  1 month.a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.The acceptable length of the extended period of time must be agreed upon by the investigator and the Medical Monitor.b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed.c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.Patients can be re-challenged with tiragolumab and atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor.a a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.The acceptable length of the extended period of time must be agreed upon by the investigator and the Medical Monitor.b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed.c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.Patients can be re-challenged with tiragolumab and atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor.

Management Guidelines for Infusion-Related Reactions
Event Management

IRR, Grade 1
Reduce infusion rate to half the rate being given at the time of event onset.
After the event has resolved, the investigator should wait for 30 minutes while delivering the infusion at the reduced rate.
If the infusion is tolerated at the reduced rate for 30 minutes after symptoms have resolved, the infusion rate may be increased to the original rate.
After symptoms have resolved to baseline, resume infusion at half the rate being given at the time of event onset.
For subsequent infusions, consider administration of oral premedication with antihistamines, antipyretic medications, and/or analgesics and monitor closely for IRRs.

IRR, Grade 3 or 4 Stop infusion.
Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, antipyretic medication, glucocorticoids, epinephrine, bronchodilators, oxygen, IV fluids).Permanently discontinue tiragolumab or atezolizumab and contact Medical Monitor.a IRR = infusion-related reaction.a Resumption of tiragolumab or atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the event.Patients can be re-challenged with tiragolumab or atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor.

Event Management
Grade 1 a Fever b with or without constitutional symptoms • Immediately interrupt infusion.
• Upon symptom resolution, wait for 30 minutes and then restart infusion at half the rate being given at the time of event onset.• If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate may be increased to the original rate.• If symptoms recur, discontinue infusion of this dose.
• Administer symptomatic treatment, c including maintenance of IV fluids for hydration.
• In case of rapid decline or prolonged CRS (> 2 days) or in patients with significant symptoms and/or comorbidities, consider managing as per Grade 2. • For subsequent infusions, consider administration of oral premedication with antihistamines, anti-pyretics, and/or analgesics, and monitor closely for CRS.
Grade 2 a Fever b with at least one of the following: • Immediately interrupt infusion.
• Upon symptom resolution, wait for 30 minutes and then restart infusion at half the rate being given at the time of event onset.Administer IV fluids as clinically indicated, and manage constitutional symptoms and organ toxicities as per institutional practice.Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).If no improvement within 24 hours, initiate workup and assess for signs and symptoms of HLH or MAS as described in this appendix.
Consider anti-cytokine therapy.
Consider hospitalization until complete resolution of symptoms.
If no improvement within 24 hours, manage as per Grade 3, that is, hospitalize patient (monitoring in the ICU is recommended), permanently discontinue tiragolumab and atezolizumab, and contact Medical Monitor.
If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose of tiragolumab and atezolizumab may be administered.For subsequent infusions, consider administration of oral premedication with antihistamines, antipyretics, and/or analgesics and monitor closely for CRS.For hypotension, administer IV fluid bolus and vasopressor as needed.Monitor cardiopulmonary and other organ function closely; monitoring in the ICU is recommended.Administer IV fluids as clinically indicated, and manage constitutional symptoms and organ toxicities as per institutional practice.Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).If no improvement within 24 hours, initiate workup and assess for signs and symptoms of HLH or MAS as described in this appendix.Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or dexamethasone 10 mg every 6 hours).
Consider anti-cytokine therapy.
Hospitalize patient until complete resolution of symptoms.If no improvement within 24 hours, manage as per Grade 4, that is, admit patient to ICU and initiate hemodynamic monitoring, mechanical ventilation, and/or IV fluids and vasopressors as needed; for patients who are refractory to anti-cytokine therapy, experimental treatments may be considered at the discretion of the investigator and in consultation with the Medical Monitor.Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis).If no improvement within 24 hours, initiate workup and assess for signs and symptoms of HLH or MAS as described in this appendix.Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or dexamethasone 10 mg every 6 hours).
Consider anti-cytokine therapy.For patients who are refractory to anti-cytokine therapy, experimental treatments may be considered at the discretion of the investigator and in consultation with the Medical Monitor.investigator and the Medical Monitor.b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed.c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.Patients can be rechallenged with tiragolumab and atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor.

Management Guidelines for Dermatologic Events
Event Management Dermatologic event, Grade 1 • Continue tiragolumab and atezolizumab.
• Consider treatment with topical corticosteroids and/or other symptomatic therapy (e.g., antihistamines).
• Consider patient referral to dermatologist for evaluation and, if indicated, biopsy.• Initiate treatment with topical corticosteroids.
• Consider treatment with higher-potency topical corticosteroids if event does not improve.

Dermatologic event, Grade 3
• Withhold tiragolumab and atezolizumab for up to 12 weeks after event onset.a • Refer patient to dermatologist for evaluation and, if indicated, biopsy.
• Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, increasing dose to 1-2 mg/kg/day if event does not improve within 48-72 hours.Tiragolumab and atezolizumab may be withheld for a longer period of time i.e., > 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.The acceptable length of the extended period of time must be agreed upon by the investigator and the Medical Monitor.b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed.c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.Patients can be re-challenged with tiragolumab and atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor.
Immune-mediated neuropathy, Grade 2 • Withhold tiragolumab and atezolizumab for up to 12 weeks after event onset.a Investigate etiology.• Initiate treatment as per institutional guidelines.• Initiate treatment as per institutional guidelines.

Myasthenia gravis and Guillain-Barré syndrome (any grade)
• Permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c • Refer patient to neurologist.
• Initiate treatment as per institutional guidelines.
• Consider initiation of corticosteroids equivalent to 1-2 mg/kg/day oral or IV prednisone.
a Tiragolumab and atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.The acceptable length of the extended period of time must be agreed upon by the investigator and the Medical Monitor.b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of  10 mg/day oral prednisone before tiragolumab and atezolizumab can be resumed.c Resumption of tiragolumab and atezolizumab may be considered in patients who are deriving benefit and have fully recovered from the immune-mediated event.Patients can be rechallenged with tiragolumab and atezolizumab only after approval has been documented by both the investigator (or an appropriate delegate) and the Medical Monitor.
• If symptoms recur, discontinue infusion of this dose.• Administer symptomatic treatment.c For hypotension, administer IV fluid bolus as needed.Monitor cardiopulmonary and other organ function closely (in the ICU, if appropriate).
If symptoms do not resolve to Grade 1 or better for 3 consecutive days, contact Medical Monitor.Permanently discontinue tiragolumab and atezolizumab and contact MedicalMonitor.e Administer symptomatic treatment.c Permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.e Administer symptomatic treatment.c Admit patient to ICU and initiate hemodynamic monitoring, mechanical ventilation, and/or IV fluids and vasopressors as needed.Monitor other organ function closely.Manage constitutional symptoms and organ toxicities as per institutional practice.
Hospitalize patient until complete resolution of symptoms.ASTCT= American Society for Transplantation and Cellular Therapy; BiPAP = bi-level positive airway pressure; CAR = chimeric antigen receptor; CPAP = continuous positive airway pressure; CRS = cytokine-release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; eCRF = electronic Case Report Form; HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; MAS = macrophage activation syndrome; NCCN = National Cancer Comprehensive Network; NCI = National Cancer Institute.The management guidelines have been adapted from NCCN guidelines for management of CAR Tcell-related toxicities (Version 2.2019).a Grading system for management guidelines is based on the ASTCT CRS consensus grading scale.NCI CTCAE v5.0 and the ASTCT CRS consensus grading scale should be used when reporting severity of CRS on the Adverse Event eCRF.NCI CTCAE v5.0 should be used when reporting severity of organ toxicities associated with CRS on the dedicated Cytokine-Release Syndrome eCRF.Organ toxicities associated with CRS should not influence overall CRS grading.

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• If event resolves to Grade 1 or better, resume tiragolumab and atezolizumab.b • If event does not resolve to Grade 1 or better while withholding tiragolumab and atezolizumab, permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c Additional guidance for Stevens-Johnson syndrome or toxic epidermal necrolysis: • Withhold tiragolumab and atezolizumab for suspected Stevens-Johnson syndrome or toxic epidermal necrolysis.• Confirm diagnosis by referring patient to a specialist (dermatologist, ophthalmologist, or urologist as relevant) for evaluation and, if indicated, biopsy.• Follow the applicable treatment and management guidelines above.• If Stevens-Johnson syndrome or toxic epidermal necrolysis is confirmed, permanently discontinue tiragolumab and atezolizumab.a

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• If event resolves to Grade 1 or better, resume tiragolumab and atezolizumab.b • If event does not resolve to Grade 1 or better while withholding tiragolumab and atezolizumab, permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c Permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c Withhold tiragolumab and atezolizumab for up to 12 weeks after event onset a and contact Medical Monitor.Refer patient to cardiologist.Initiate treatment as per institutional guidelines and consider antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as appropriate.Consider treatment with corticosteroids equivalent to 1-2 mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.If event resolves to Grade 1 or better, resume tiragolumab and atezolizumab.b If event does not resolve to Grade 1 or better while withholding tiragolumab and atezolizumab, permanently discontinue tiragolumab and atezolizumab and contact Medical Monitor.c /kg/day IV methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent upon improvement.If event does not improve within 48 hours after initiating corticosteroids, consider adding an immunosuppressive agent.If event resolves to Grade 1 or better, taper corticosteroids over  1 month.ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device.